The efficacy of bevacizumab plus erlotinib (B+E) in patients (pts) with renal medullary carcinoma (RMC).

Abstract

303 Background: RMC is a rare and highly aggressive malignancy with a median overall survival (OS) of only 13 months from diagnosis. RMC is thought to be completely refractory to the targeted therapies used against clear cell renal cell carcinoma and the recommended standard of care therapy is platinum-based cytotoxic chemotherapy, which only produces a best response rate of 29% in the first line setting (Shah et al. BJU Int., 2017). Comprehensive molecular profiling of RMC tissues revealed a decrease in genes related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and an increase in genes involved in fatty acid synthesis, demonstrating a reliance on aerobic glycolysis to meet cellular bioenergetics needs (Msaouel et al. Cancer Cell, 2020). The combination of B+E is particularly effective in tumors such as fumarate hydratate – deficient renal cell carcinomas, which also rely on aerobic glycolysis. We therefore hypothesized that B+E would show clinical efficacy against RMC. Methods: We analyzed 10 pts with RMC treated with B+E at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Clinical-grade next generation genome sequencing for gene mutations, copy number alterations and fusions was performed in 6/10 pts using the Oncomine platform. Results: Between 05/2005 and 09/2020, we identified 10 pts with RMC that were treated with B+E (Table). B+E produced a partial response in 2/10 pts (20%) and stable disease as best response in 6/10 pts (60%), resulting in a median progression-free survival of 3.5 months (mo) with 95% CI 1.8 – 5.2 mo. Decrease in tumor burden was noted even in patients that had received 3+ prior therapies and irrespective of genomic alterations. The median overall survival (OS) from B+E initiation was 7.3 mo (95% CI 5.4 – 9.1) and the median OS from diagnosis was 20.8 mo (95% CI 15.4 – 26.1). B+E was well tolerated with no grade ≥ 4 AEs and only one grade 3 AE (skin rash). Dose reduction was only needed in 1/10 pts. Conclusions: B+E is clinically active and well tolerated in heavily pre-treated pts with RMC and is therefore a viable therapeutic option for this lethal disease. However, pts ultimately relapse and further investigation is needed to elucidate mechanisms of resistance and determine how to optimally target metabolic vulnerabilities in RMC. [Table: see text]